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Adler A.,Central University of Costa Rica | Geiger S.,Central University of Costa Rica | Keil A.,Charite - Medical University of Berlin | Bias H.,Charite - Medical University of Berlin | And 5 more authors.
BMC Gastroenterology | Year: 2015

Background: Despite strong recommendations for colorectal cancer (CRC) screening, participation rates are low. Understanding factors that affect screening choices is essential to developing future screening strategies. Therefore, this study assessed patient willingness to use non-invasive stool or blood based screening tests after refusing colonoscopy. Methods: Participants were recruited during regular consultations. Demographic, health, psychological and socioeconomic factors were recorded. All subjects were advised to undergo screening by colonoscopy. Subjects who refused colonoscopy were offered a choice of non-invasive tests. Subjects who selected stool testing received a collection kit and instructions; subjects who selected plasma testing had a blood draw during the office visit. Stool samples were tested with the Hb/Hp Complex Elisa test, and blood samples were tested with the Epi proColon® 2.0 test. Patients who were positive for either were advised to have a diagnostic colonoscopy. Results: 63 of 172 subjects were compliant to screening colonoscopy (37%). 106 of the 109 subjects who refused colonoscopy accepted an alternative non-invasive method (97%). 90 selected the Septin9 blood test (83%), 16 selected a stool test (15%) and 3 refused any test (3%). Reasons for blood test preference included convenience of an office draw, overall convenience and less time consuming procedure. Conclusions: 97% of subjects refusing colonoscopy accepted a non-invasive screening test of which 83% chose the Septin9 blood test. The observation that participation can be increased by offering non-invasive tests, and that a blood test is the preferred option should be validated in a prospective trial in the screening setting. © 2014 Adler et al.; licensee BioMed Central Ltd.


Detection of colorectal cancer at an early stage has been shown to significantly decrease mortality from the disease, while the advent of effective therapies for late-stage colorectal cancer make the detection of colorectal cancer at any stage a critical step in further reducing colorectal cancer mortality. Availability of a blood-based test for colorectal cancer is expected to improve screening compliance in the general population. Through DNA methylation-sensitive, restriction enzyme-based biomarker discovery, we identified a region of the Septin 9 gene that is methylated in over 90% of colorectal cancer tissues with little or no methylation seen in normal colon tissue and other controls. Specific detection of colorectal cancer DNA using the Septin 9 methylation biomarker ( m SEPT9) was demonstrated in multiple studies of plasma from colorectal cancer patients and colonoscopy-verified negative controls. A prospective, population-based trial to determine the clinical performance of m SEPT9 in colorectal cancer screening guideline-eligible individuals has recently been completed, with the results to be published in the near future. The potential pitfalls and lessons learned in the multiyear process of developing the m SEPT9 biomarker from initial discovery to commercialization are described in this article. © 2010 Future Medicine Ltd.


Wasserkort R.,Epigenomics AG | Wasserkort R.,Delta Vir GmbH | Kalmar A.,Semmelweis University | Valcz G.,Semmelweis University | And 9 more authors.
BMC Cancer | Year: 2013

Background: The septin 9 gene (SEPT9) codes for a GTP-binding protein associated with filamentous structures and cytoskeleton formation. SEPT9 plays a role in multiple cancers as either an oncogene or a tumor suppressor gene. Regulation of SEPT9 expression is complex and not well understood; however, hypermethylation of the gene was recently introduced as a biomarker for early detection of colorectal cancer (CRC) and has been linked to cancer of the breast and of the head and neck. Because the DNA methylation landscape of different regions of SEPT9 is poorly understood in cancer, we analyzed the methylation patterns of this gene in distinct cell populations from normal and diseased colon mucosa.Methods: Laser capture microdissection was performed to obtain homogeneous populations of epithelial and stromal cells from normal, adenomatous, and tumorous colon mucosa. Microdissected samples were analyzed using direct bisulfite sequencing to determine the DNA methylation status of eight regions within and near the SEPT9 gene. Septin-9 protein expression was assessed using immunohistochemistry (IHC).Results: Regions analyzed in SEPT9 were unmethylated in normal tissue except for a methylation boundary detected downstream of the largest CpG island. In adenoma and tumor tissues, epithelial cells displayed markedly increased DNA methylation levels (>80%, p <0.0001) in only one of the CpG islands investigated. SEPT9 methylation in stromal cells increased in adenomatous and tumor tissues (≤50%, p <0.0001); however, methylation did not increase in stromal cells of normal tissue close to the tumor. IHC data indicated a significant decrease (p <0.01) in Septin-9 protein levels in epithelial cells derived from adenoma and tumor tissues; Septin-9 protein levels in stromal cells were low in all tissues.Conclusions: Hypermethylation of SEPT9 in adenoma and CRC specimens is confined to one of several CpG islands of this gene. Tumor-associated aberrant methylation originates in epithelial cells; stromal cells appear to acquire hypermethylation subsequent to epithelial cells, possibly through field effects. The region in SEPT9 with disease-related hypermethylation also contains the CpGs targeted by a novel blood-based screening test (Epi proColon®), providing further support for the clinical relevance of this biomarker. © 2013 Wasserkort et al.; licensee BioMed Central Ltd.


Church T.R.,University of Minnesota | Wandell M.,CRQ Insight LLC | Rosch T.,University of Hamburg | Osborn N.,Atlanta Gastroenterology Associates | And 5 more authors.
Clinical Gastroenterology and Hepatology | Year: 2014

Background & Aims: We investigated rates of detection of proximal serrated lesions in a cohort of average-risk patients undergoing screening colonoscopies. Methods: We reviewed results from screening colonoscopies performed by attending gastroenterologists at 32 endoscopy centers from 2008-2010. Pathology slides were interpreted at the individual centers. For this analysis, serrated lesions included hyperplastic polyps larger than 10 mm, those interpreted as sessile serrated adenomas (or sessile serrated polyp), and traditional serrated adenomas. Rates of detection for conventional adenomas and serrated lesions were compared among centers. Results: A total of 5778 lesions were detected in 7215 screening colonoscopies. Of the 5548 lesions with pathology results, 3008 (54.2%) were conventional adenomas, 350 (6.3%) were serrated, and 232 (4.2%) were proximal serrated. The proportion of colonoscopies with at least 1 proximal serrated lesion was 2.8% (range among centers, 0%-9.8%). The number of serrated lesions per colonoscopy ranged from 0.00-0.11 (average, 0.05 ± 0.25). Overall lesion detection rates correlated with proximal serrated lesion detection rates (R= 0.91, P < .0001); conventional adenoma and proximal serrated lesion detection rates also correlated (R= .43, P= .025). The detection rate of proximal serrated lesions differed significantly among centers (P < .0001); odds ratios for detection ranged from 0-0.79. Some centers' pathologists never identified proximal serrated lesions as sessile serrated adenomas/polyps. Conclusions: In an average-risk screening cohort, detection of proximal serrated lesions varied greatly among endoscopy centers. There was also substantial variation among pathologists in identification of sessile serrated adenomas/polyps. Nationally, a significant proportion of proximal serrated lesions may be missed during colonoscopy examination or incorrectly identified during pathology assessment. ClinicalTrials.gov Number: NCT00855348. © 2014 AGA Institute.


Tanzer M.,TU Munich | Balluff B.,TU Munich | Distler J.,Epigenomics Inc. | Hale K.,Epigenomics Inc. | And 7 more authors.
PLoS ONE | Year: 2010

Background: Screening for colorectal cancer (CRC) has shown to reduce cancer-related mortality, however, acceptance and compliance to current programmes are poor. Developing new, more acceptable non-invasive tests for the detection of cancerous and precancerous colorectal lesions would not only allow preselection of individuals for colonoscopy, but may also prevent cancer by removal of precancerous lesions. Methods: Plasma from 128 individuals (cohort I - exploratory study: 73 cases / 55 controls ) was used to test the performance of a single marker, SEPT9, using a real-time quantitative PCR assay. To validate performance of SEPT9, plasma of 76 individuals (cohort II - validation study: 54 cases / 22 controls) was assessed. Additionally, improvement of predictive capability considering SEPT9 and additionally ALX4 methylation was investigated within these patients. Results: In both cohorts combined, methylation of SEPT9 was observed in 9% of controls (3/33), 29% of patients with colorectal precancerous lesions (27/94) and 73% of colorectal cancer patients (24/33). The presence of both SEPT9 and ALX4 markers was analysed in cohort II and was observed in 5% of controls (1/22) and 37% of patients with polyps (18/49). Interestingly, also 3/5 (60%) patients with colorectal cancer were tested positive by the two marker panel in plasma. Conclusions: While these data confirm the detection rate of SEPT9 as a biomarker for colorectal cancer, they also show that methylated DNA from advanced precancerous colorectal lesions can be detected using a panel of two DNA methylation markers, ALX4 and SEPT9. If confirmed in larger studies these data indicate that screening for colorectal precancerous lesions with a blood-based test may be as feasible as screening for invasive cancer. © 2010 Tänzer et al.

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